A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6.
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23 mars 2021
- doi: 10.1073/pnas.2016730118
- issn: 0027-8424
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info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.2016730118
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info:eu-repo/semantics/altIdentifier/pmid/33723042
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info:eu-repo/semantics/altIdentifier/eissn/1091-6490
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info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_F26C5AEBA2337
info:eu-repo/semantics/openAccess , CC BY 4.0 , https://creativecommons.org/licenses/by/4.0/
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Paralysis agitans Shaking palsy Palsy, Shaking Parkinson disease Parkinsonism Melting Pattern Model Periodicity Natural cycles Cyclic theory Interactions, Protein-protein Protein interactions Toxicity Poisoning illnessCiter ce document
K. McGrath et al., « A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6. », Serveur académique Lausannois, ID : 10.1073/pnas.2016730118
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Ykt6 is a soluble N-ethylmaleimide sensitive factor activating protein receptor (SNARE) critically involved in diverse vesicular fusion pathways. While most SNAREs rely on transmembrane domains for their activity, Ykt6 dynamically cycles between the cytosol and membrane-bound compartments where it is active. The mechanism that regulates these transitions and allows Ykt6 to achieve specificity toward vesicular pathways is unknown. Using a Parkinson's disease (PD) model, we found that Ykt6 is phosphorylated at an evolutionarily conserved site which is regulated by Ca 2+ signaling. Through a multidisciplinary approach, we show that phosphorylation triggers a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. In the phosphorylated open form, the spectrum of protein interactions changes, leading to defects in both the secretory and autophagy pathways, enhancing toxicity in PD models. Our studies reveal a mechanism by which Ykt6 conformation and activity are regulated with potential implications for PD.